Breast cancer is the second leading cause of cancer death among women in the United States and is the leading cause of death among women aged 30-70. (Abeloff, M. D., Curr. Opin. Oncol., 8:447-448 (1996) ). The inheritance of germ-line mutations in autosomal dominant susceptibility genes appears to be responsible for 5-10% of all breast cancer cases (Fitzgerald, M. G., et al., New Engl. J. Med., 334:143-149 (1996) ), and up to 36% of the cases diagnosed before age 30. BRCA1 was the first isolated breast cancer susceptibility gene (Langston, A. A., et al., New Engl. J. Med., 334:137-142 (1996); Couch, F. J. and Weber, B. L., Hum. Mutat., 8:8-18 (1996) ) and mutations in BRCA1 alone account for approximately 45% of the families with high incidence of breast and ovarian cancer (Chen, Y. M., et al., Science, 272:125-126 (1996); Sully, R., et al., Science, 272:123-126 (1996) ). In addition, a second breast cancer susceptibility gene, BRCA2, has been isolated recently (Wooster, R., et al., Nature, 378:789-792 (1995); Tavtigian, S. V., et al., Nat. Genet., 12:333-337 (1996) ).
However, the majority of breast carcinomas appear to be sporadic and have a complex accumulation of molecular and cellular abnormalities that constitute the malignant phenotype. A number of somatic gene alterations, such as loss of expression of specific tumor suppressor genes, have been found to occur in primary human breast tumors (Borg, A., et al., Cancer Res., 52:2991-2994 (1992); Eeles, R. A., et al., Cancer Surveys, 25:101-124 (1995) ). Additionally, there is considerable evidence that genetic alterations in growth factor signaling pathways can contribute to human breast malignancies. In this regard, activation of different proto-oncogenes has been found in primary breast tumor (Berns, E. M., et al., Cancer Res., 52:1036-1039 (1992); Borg, A., et al., Brit. J. Cancer, 63:136-142 (1991); Gullick, W. J., et al., Brit. J. Cancer, 63:434-438 (1991) ). Thus, there is considerable importance in identifying, at a molecular level, factors that contribute to the progression from normal growth towards malignancy.